This research is concerned with molecular mechanisms of cell transformation by the Rous sarcoma virus src oncogene. Although much is known about viral src, very little is understood about how this oncogene induces cell transformation. To address this problem, mammalian genes encoding cellular proteins that interact with viral src protein in promoting or suppressing transformation will be selectively isolated. These cellular genes are postulated to encode three distinct classes of proteins. One class consists of substrates that are primary targets for the protein-tyrosine kinase activity of the src gene product; phosphorylation of these substrates is presumed to be the initial step leading to transformation. Mutant cellular genes encoding substrates will be molecularly cloned by complementation of viral src mutants that are partially transformation-defective. A second class if comprised of effector proteins that are not substrates of the viral src kinase but are involved in other ways in cellular pathways mediating transformation, possibly as intermediates in a series or cascade of reactions. Cellular genes encoding effector proteins will be cloned by complementation of cellular mutants that are defective for transformation by wild- type viral src. The third class of proteins, in contrast to the first two classes, is involved in suppressing cell transformation. Cellular genes encoding proteins that suppress transformation by wild-type viral src in a dominant manner will be cloned from transformation-resistant cells. Proposed genetic strategies are designed to ensure selection of cellular genes involved in transformation by viral src without excluding genes coding for unexpected classes of proteins. The ultimate goal of this research is characterization of proteins encoded in the molecular clones for the purpose of understanding their functions in normal and transformed cells. Knowledge of how viral src subverts normal growth control at the molecular level may lead to potential approaches for controlling neoplasia in humans.